QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (67) Citing Articles via Google Scholar Google Scholar Articles by Tomita, T. Articles by Iwatsubo, T. Search for Related Content PubMed PubMed Citation Articles by Tomita, T. Articles by Iwatsubo, T.

 Previous Article  |  Next Article 

The Journal of Neuroscience, December 15, 1999, 19(24):10627-10634

C Terminus of Presenilin Is Required for Overproduction of Amyloidogenic A42 through Stabilization and Endoproteolysis of Presenilin

Taisuke Tomita¹, Rie Takikawa¹, Akihiko Koyama¹, Yuichi Morohashi¹, Nobumasa Takasugi¹, Takaomi C. Saido², Kei Maruyama³, and Takeshi Iwatsubo¹

¹ Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyoku Tokyo 113-0033, Japan, ² Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan, and ³ Laboratory of Molecular Biology, Tokyo Institute of Psychiatry, Kamikitazawa, Setagayaku, Tokyo 156-8585, Japan

Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD) by increasing production of the amyloidogenic form of amyloid  peptides ending at residue 42 (A42). To identify a PS subdomain responsible for overproduction of A42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N141I FAD mutation. Deletion or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N141I FAD mutation abrogated the increase in A42 secretion, and A42 overproduction was dependent on the stabilization and endoproteolysis of PS2. The same C-terminal modifications in PS1 produced similar effects. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of A42 through stabilization of endoproteolytic PS derivatives and that these derivatives may be the pathologically active species of PS that cause FAD.

Key words: presenilin 2; presenilin 1; C terminus; amyloid  peptide; A42; endoproteolysis; stabilization; familial Alzheimer's disease

---

Copyright © 1999 Society for Neuroscience  0270-6474/99/192410627-08$05.00/0

This article has been cited by other articles:

				I. Hayashi, S. Takatori, Y. Urano, H. Iwanari, N. Isoo, S. Osawa, M. A. Fukuda, T. Kodama, T. Hamakubo, T. Li, et al. Single Chain Variable Fragment against Nicastrin Inhibits the {gamma}-Secretase Activity J. Biol. Chem., October 9, 2009; 284(41): 27838 - 27847. [Abstract] [Full Text] [PDF]

				C. Sato, S. Takagi, T. Tomita, and T. Iwatsubo The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the {gamma}-Secretase J. Neurosci., June 11, 2008; 28(24): 6264 - 6271. [Abstract] [Full Text] [PDF]

				N. Isoo, C. Sato, H. Miyashita, M. Shinohara, N. Takasugi, Y. Morohashi, S. Tsuji, T. Tomita, and T. Iwatsubo Abeta42 Overproduction Associated with Structural Changes in the Catalytic Pore of {gamma}-Secretase: COMMON EFFECTS OF PEN-2 N-TERMINAL ELONGATION AND FENOFIBRATE J. Biol. Chem., April 27, 2007; 282(17): 12388 - 12396. [Abstract] [Full Text] [PDF]

				C. Sato, Y. Morohashi, T. Tomita, and T. Iwatsubo Structure of the Catalytic Pore of {gamma}-Secretase Probed by the Accessibility of Substituted Cysteines. J. Neurosci., November 15, 2006; 26(46): 12081 - 12088. [Abstract] [Full Text] [PDF]

				Y. Morohashi, T. Kan, Y. Tominari, H. Fuwa, Y. Okamura, N. Watanabe, C. Sato, H. Natsugari, T. Fukuyama, T. Iwatsubo, et al. C-terminal Fragment of Presenilin Is the Molecular Target of a Dipeptidic {gamma}-Secretase-specific Inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-Butyl Ester) J. Biol. Chem., May 26, 2006; 281(21): 14670 - 14676. [Abstract] [Full Text] [PDF]

				H. Shiraishi, T. Marutani, H.-Q. Wang, Y. Maeda, Y. Kurono, A. Takashima, W. Araki, M. Nishimura, K. Yanagisawa, and H. Komano Reconstitution of {gamma}-secretase by truncated presenilin (PS) fragments revealed that PS C-terminal transmembrane domain is critical for formation of {gamma}-secretase complex Genes Cells, January 1, 2006; 11(1): 83 - 93. [Abstract] [Full Text] [PDF]

				N. Watanabe, T. Tomita, C. Sato, T. Kitamura, Y. Morohashi, and T. Iwatsubo Pen-2 Is Incorporated into the {gamma}-Secretase Complex through Binding to Transmembrane Domain 4 of Presenilin 1 J. Biol. Chem., December 23, 2005; 280(51): 41967 - 41975. [Abstract] [Full Text] [PDF]

				Y. Urano, I. Hayashi, N. Isoo, P. C. Reid, Y. Shibasaki, N. Noguchi, T. Tomita, T. Iwatsubo, T. Hamakubo, and T. Kodama Association of active {gamma}-secretase complex with lipid rafts J. Lipid Res., May 1, 2005; 46(5): 904 - 912. [Abstract] [Full Text] [PDF]

				M. Niimura, N. Isoo, N. Takasugi, M. Tsuruoka, K. Ui-Tei, K. Saigo, Y. Morohashi, T. Tomita, and T. Iwatsubo Aph-1 Contributes to the Stabilization and Trafficking of the {gamma}-Secretase Complex through Mechanisms Involving Intermolecular and Intramolecular Interactions J. Biol. Chem., April 1, 2005; 280(13): 12967 - 12975. [Abstract] [Full Text] [PDF]

				Y. Qi-Takahara, M. Morishima-Kawashima, Y. Tanimura, G. Dolios, N. Hirotani, Y. Horikoshi, F. Kametani, M. Maeda, T. C. Saido, R. Wang, et al. Longer Forms of Amyloid {beta} Protein: Implications for the Mechanism of Intramembrane Cleavage by {gamma}-Secretase J. Neurosci., January 12, 2005; 25(2): 436 - 445. [Abstract] [Full Text] [PDF]

				A. Bergman, H. Laudon, B. Winblad, J. Lundkvist, and J. Naslund The Extreme C Terminus of Presenilin 1 Is Essential for {gamma}-Secretase Complex Assembly and Activity J. Biol. Chem., October 29, 2004; 279(44): 45564 - 45572. [Abstract] [Full Text] [PDF]

				I. Hayashi, Y. Urano, R. Fukuda, N. Isoo, T. Kodama, T. Hamakubo, T. Tomita, and T. Iwatsubo Selective Reconstitution and Recovery of Functional {gamma}-Secretase Complex on Budded Baculovirus Particles J. Biol. Chem., September 3, 2004; 279(36): 38040 - 38046. [Abstract] [Full Text] [PDF]

				Y. Takahashi, I. Hayashi, Y. Tominari, K. Rikimaru, Y. Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo Sulindac Sulfide Is a Noncompetitive gamma -Secretase Inhibitor That Preferentially Reduces Abeta 42 Generation J. Biol. Chem., May 9, 2003; 278(20): 18664 - 18670. [Abstract] [Full Text] [PDF]

				N. Takasugi, Y. Takahashi, Y. Morohashi, T. Tomita, and T. Iwatsubo The Mechanism of gamma -Secretase Activities through High Molecular Weight Complex Formation of Presenilins Is Conserved in Drosophila melanogaster and Mammals J. Biol. Chem., December 13, 2002; 277(51): 50198 - 50205. [Abstract] [Full Text] [PDF]

				R. Rozmahel, H. T. J. Mount, F. Chen, V. Nguyen, J. Huang, S. Erdebil, J. Liauw, G. Yu, H. Hasegawa, Y. Gu, et al. Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype PNAS, October 29, 2002; 99(22): 14452 - 14457. [Abstract] [Full Text] [PDF]

				Y. Morohashi, N. Hatano, S. Ohya, R. Takikawa, T. Watabiki, N. Takasugi, Y. Imaizumi, T. Tomita, and T. Iwatsubo Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4 J. Biol. Chem., April 19, 2002; 277(17): 14965 - 14975. [Abstract] [Full Text] [PDF]

				M. A. Leissring, T. R. Yamasaki, W. Wasco, J. D. Buxbaum, I. Parker, and F. M. LaFerla Calsenilin reverses presenilin-mediated enhancement of calcium signaling PNAS, July 18, 2000; 97(15): 8590 - 8593. [Abstract] [Full Text] [PDF]

				H. Steiner, T. Revesz, M. Neumann, H. Romig, M. G. Grim, B. Pesold, H. A. Kretzschmar, J. Hardy, J. L. Holton, R. Baumeister, et al. A Pathogenic Presenilin-1 Deletion Causes Abberrant Abeta 42 Production in the Absence of Congophilic Amyloid Plaques J. Biol. Chem., March 2, 2001; 276(10): 7233 - 7239. [Abstract] [Full Text] [PDF]

				H. Iwata, T. Tomita, K. Maruyama, and T. Iwatsubo Subcellular Compartment and Molecular Subdomain of beta -Amyloid Precursor Protein Relevant to the Abeta 42-promoting Effects of Alzheimer Mutant Presenilin 2 J. Biol. Chem., June 8, 2001; 276(24): 21678 - 21685. [Abstract] [Full Text] [PDF]

				E.-K. Choi, N. F. Zaidi, J. S. Miller, A. C. Crowley, D. E. Merriam, C. Lilliehook, J. D. Buxbaum, and W. Wasco Calsenilin Is a Substrate for Caspase-3 That Preferentially Interacts with the Familial Alzheimer's Disease-associated C-terminal Fragment of Presenilin 2 J. Biol. Chem., May 25, 2001; 276(22): 19197 - 19204. [Abstract] [Full Text] [PDF]

				T. Tomita, T. Watabiki, R. Takikawa, Y. Morohashi, N. Takasugi, R. Kopan, B. De Strooper, and T. Iwatsubo The First Proline of PALP Motif at the C Terminus of Presenilins Is Obligatory for Stabilization, Complex Formation, and gamma -Secretase Activities of Presenilins J. Biol. Chem., August 24, 2001; 276(35): 33273 - 33281. [Abstract] [Full Text] [PDF]

				C. A. Saura, T. Tomita, S. Soriano, M. Takahashi, J.-Y. Leem, T. Honda, E. H. Koo, T. Iwatsubo, and G. Thinakaran The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Abeta 42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants J. Biol. Chem., May 26, 2000; 275(22): 17136 - 17142. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help